The present invention relates to novel macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to novel 11,12-lactone ketolides, 14-membered macrolides, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
Macrolide antibiotics play a therapeutically important role, particularly with the emergence of new pathogens. Structural differences are related to the size of the lactone ring and to the number and nature (neutral or basic) of the sugars. Macrolides are classified according to the size of the lactone ring (12, 14, 15 or 16 atoms). The macrolide antibiotic families (14-, 15- and 16-membered ring derivatives) exhibit a wide range of characteristics (antibacterial spectrum, side-effects and bioavailability). Among the commonly used macrolides are erythromycin, clarithromycin and azithromycin.
Erythromycins A through D, represented by formula (E) as illustrated below, 
are well-known and potent antibacterial agents and are used widely to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
EP 559896 of Kashimura et al, published Nov. 11, 1991, discloses 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure. Also, International Application WO 93/21200, published Apr. 22, 1992, of Asaka et al. discloses 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure.
Recently erythromycin derivatives containing a variety of substituents at the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549 and 6,075,011 as well as published International Application WO 00/78773. Furthermore, Ma et. al. have described erythromycin derivatives with aryl groups tethered to the C-6 position in J. Med Chem., 44, pp 4137-4156 (2001).
International Application WO 02/16380 of Angehrn et al, discloses 14-membered macrolides as do published International Applications WO 02/50091 and WO 02/50092. Also, U.S. Pat. No. 6,124,269 discloses 2-halo-6-O-substituted ketolide; derivatives
The present invention provides a novel class 2-substituted 14-membered macrolide compounds possessing antibacterial activity toward Gram positive and Gram negative bacteria as well as macrolide resistant Gram positives. The compounds of the present invention are represented by the general formula I as illustrated below 
as well as the pharmaceutically acceptable salts, esters or prodrugs thereof.
In formula I above:
L is selected from the group consisting of:
(1) xe2x80x94CH(OH)CH3;
(2) C1-C6 alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(3) C2-C6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
(4) C2-C6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl;
R1 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl, each optionally substituted with one or more substituents selected from the group consisting of:
(1) halogen;
(2) aryl;
(3) substituted aryl;
(4) heteroaryl;
(5) substituted heteroaryl;
(6) xe2x80x94Oxe2x80x94R5, where R5 is selected from the group consisting of:
a. hydrogen;
b. aryl;
c. substituted aryl;
d. heteroaryl; and
e. substituted heteroaryl;
(7) xe2x80x94Oxe2x80x94C1-C6-alkyl-R5, where R5 is as previously defined;
(8) xe2x80x94Oxe2x80x94C2-C6-alkenyl-R5, where R5 is as previously defined;
(9) xe2x80x94Oxe2x80x94C2-C6-alkynyl-R5, where R5 is as previously defined; and
(10) xe2x80x94N6R7, where R6 and R7 are each independently selected from the group consisting of: hydrogen; C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; and C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic:and substituted heterocyclic; or R6R7 taken together with the nitrogen atom to which they are attached form a 3- to 7-membered ring which may optionally contain one or more hetero functions selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(C1-C6-alkyl)xe2x80x94, xe2x80x94N(aryl)-, xe2x80x94N(heteroaryl)-, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 and xe2x80x94S(O)2xe2x80x94;
R2 is selected from the group consisting of:
(1) hydrogen;
(2) C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of:
a. halogen;
b. aryl;
c. substituted aryl;
d. heterocyclic;
e. substituted heterocyclic;
f. xe2x80x94Oxe2x80x94R3, where R3 is selected from the group consisting of:
i. hydrogen;
ii. aryl;
iii. substituted aryl;
iv. heteroaryl; and
v. substituted heteroaryl;
g. xe2x80x94Oxe2x80x94C1-C6-alkyl-R3, where R3is as previously defined;
h. xe2x80x94Oxe2x80x94C2-C6-alkenyl-R3, where R3 is as previously defined;
i. xe2x80x94Oxe2x80x94C2-C6-alkynyl-R3, where R3 is as previously defined; and
j. xe2x80x94NR6R7, where R6 and R7 are as previously defined;
(3) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of:
a. halogen;
b. aryl;
c. substituted aryl;
d. heterocyclic;
e. substituted heterocyclic;
f. xe2x80x94Oxe2x80x94R3, where R3 is as previously defined;
g. xe2x80x94Oxe2x80x94C1-C6-alkyl-R3, where R3is as previously defined;
h. xe2x80x94Oxe2x80x94C2-C6-alkenyl-R3, where R3 is as previously defined;
i. xe2x80x94Oxe2x80x94C2-C6-alkynyl-R3, where R3 is as previously defined; and
j. xe2x80x94NR6R7, where R6 and R7 are as previously defined; and
(4) C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of:
a. halogen;
b. aryl;
c. substituted aryl;
d. heterocyclic;
e. substituted heterocyclic;
f. xe2x80x94Oxe2x80x94R3, where R3 is as previously defined;
g. xe2x80x94Oxe2x80x94C1-C6-alkyl-R3, where R3 is as previously defined;
h. xe2x80x94Oxe2x80x94C2-C6-alkenyl-R3, where R3 is as previously defined;
i. xe2x80x94Oxe2x80x94C2-C6-alkynyl-R3, where R3 is as previously defined; and
j. xe2x80x94NR6R7, where R6 and R7 are as previously defined;
X is selected from the group consisting of:
(1) S(O)n, where n is 0, 1, or 2; and
(2) O;
Z is selected from the group consisting of:
(1) hydrogen;
(2) halogen; and
(3) methyl;
provided that when X is S(O)n, R1 is not methyl, and Rp is hydrogen or a hydroxy protecting group.
In another aspect of the present invention there are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier and treatment of bacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed. The compounds and compositions of the present invention have antibacterial activity.
In a further aspect of the present invention there are provided processes for the preparation of bicyclic macrolide derivatives of formula I wherein L, Z, X, R1, R2 and Rp are as previously described.
A first embodiment of the present invention includes compounds represented by formula I, as illustrated above, as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
A preferred group of compounds of the present invention are those represented by formula I wherein, L is ethyl, X is sulfur, Z is fluorine, R1 is methyl and where R2 and Rp are as previously defined.
Particularly preferred compounds according to the invention are those wherein R2 is selected from the group consisting of xe2x80x94CH2CH2xe2x80x94Ar where Ar is selected from the group consisting of: 
and L, X, Z, R1 and Rp are as previously described.
Representative compounds of the invention are those selected from the group consisting of:
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=CH3, R2=xe2x80x94CH2CH2-A1 and Rp=H;
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=CH3, R2=xe2x80x94CH2CH2-A2 and Rp=H;
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=CH3, R2=xe2x80x94CH2CH2-A3 and Rp=H;
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=CH3, R2=xe2x80x94CH2CH2-A4 and Rp=H;
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=CH3, R2=xe2x80x94CH2CH2-A5 and Rp=H;
Compound of formula I: L=CH2CH3, X=O, Z=F, R1=CH3, R2=xe2x80x94CH2CH2-phenyl and Rp=H;
Compound of formula I: L=CH2CH3, X=S, Z=H, R1=xe2x80x94CH2CHCH2, R2=CH3 and Rp=H;
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=xe2x80x94CH2CHCH2, R2=CH3 and Rp=H;
Compound of formula I: L=CH2CH3, X=S; Z=H, R1=xe2x80x94CH2CHCH2-3-quinolyl, R2=CH3 and Rp=H; and
Compound of formula I: L=CH2CH3, X=S, Z=F, R1=xe2x80x94CH2CHCH2-3-quinolyl, R2=CH3 and Rp=H.
The terms xe2x80x9cC1-C3 alkyl,xe2x80x9d xe2x80x9cC1-C6 alkylxe2x80x9d or xe2x80x9cC1-C12 alkyl,xe2x80x9d as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and three, one and twelve, or one and six carbon atoms, respectively. Examples of C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl radicals; examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals; and examples of C1-C12 alkyl radicals include, but are not limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.
The terms xe2x80x9cC2-C12 alkenylxe2x80x9d or xe2x80x9cC2-C6 alkenyl,xe2x80x9d as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The terms xe2x80x9cC2-C12 alkynylxe2x80x9d or xe2x80x9cC2-C6 alkynyl;xe2x80x9d as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon triple bond by the removal of two hydrogen atoms. Representative alkynyl groups include, but are not limited to for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogen,xe2x80x9d as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term xe2x80x9chaloalkylxe2x80x9d denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, substituted lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9csubstituted aryl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO2, CN, C(O)xe2x80x94C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2-alkyl, CO2-aryl, CO2-heteroaryl, CONH2, CONHxe2x80x94C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)xe2x80x94C1-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO2-alkyl, OCO2-aryl, OCO2-heteroaryl, OCONH2, OCONHxe2x80x94C1-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)xe2x80x94C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO2-alkyl, NHCO2-aryl, NHCO2-heteroaryl, NHCONH2, NHCONHxe2x80x94C1-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO2xe2x80x94C1-C6-alkyl, SO2-aryl, SO2-heteroaryl, SO2NH2, SO2NHxe2x80x94C1-C6-alkyl, SO2NH-aryl, SO2NH-heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CH2Cl2, CH2OH, CH2CH2OH, CH2NH2, CH2SO2CH3, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-C6-alkyl-thio, or methylthiomethyl.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
The term xe2x80x9csubstituted heteroaryl,xe2x80x9d as used herein, refers to a heteroaryl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO2, CN, C(O)xe2x80x94C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2-alkyl, CO2-aryl, CO2-heteroaryl, CONH2, CONHxe2x80x94C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)xe2x80x94C1-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO2-alkyl, OCO2-aryl, OCO2-heteroaryl, OCONH2, OCONHxe2x80x94C1-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)xe2x80x94C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO2-alkyl, NHCO2-aryl, NHCO2-heteroaryl, NHCONH2, NHCONHxe2x80x94C1-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO2xe2x80x94C1-C6-alkyl, SO2-aryl, SO2-heteroaryl, SO2NH2, SO2NHxe2x80x94C1-C6-alkyl, SO2NH-aryl, SO2NH-heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CH2Cl2, CH2OH, CH2CH2OH, CH2NH2, CH2SO2CH3, aryl, heteroaryl, benzyl, enzyloxy, aryloxy, heteroaryloxy, C1-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-C6-alkyl-thio, or methylthiomethyl.
The term xe2x80x9cC3-C12-cycloalkylxe2x80x9d denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
The term xe2x80x9cheterocycloalkyl,xe2x80x9d as used herein, refers to a non-aromatic 5-, 6- or 7-membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term xe2x80x9cC1-C6 alkoxy,xe2x80x9d as used herein, refers to a C1-C6 alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term xe2x80x9cC1-C3-alkyl-amino,xe2x80x9d as used herein, refers to one or two C1-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of C1-C3-alkyl-amino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
The term xe2x80x9calkylaminoxe2x80x9d refers to a group having the structure xe2x80x94NH(C1-C12 alkyl) where C1-C12 alkyl is as previously defined.
The term xe2x80x9cdialkylaminoxe2x80x9d refers to a group having the structure xe2x80x94N(C1-C12 alkyl) (C1-C12 alkyl), where C1-C12 alkyl is as previously defined. Examples of dialkylamino are, but not limited to, dimethylamino, diethylamino, methylethylamino, piperidino, and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d represents an ester group, i.e. an alkoxy group, attached o the parent molecular moiety through a carbonyl group such as methoxycarbonyl, thoxycarbonyl, and the like.
The term xe2x80x9ccarboxaldehyde,xe2x80x9d as used herein, refers to a group of formula xe2x80x94CHO.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a group of formula xe2x80x94COOH.
The term xe2x80x9ccarboxamide,xe2x80x9d as used herein, refers to a group of formula xe2x80x94C(O)NH(C1-C12 alkyl) or xe2x80x94C(O)N(C1-C12 alkyl)(C1-C12 alkyl).
xe2x80x9cHydroxy protecting group,xe2x80x9d as used herein, refers to an easily removable group to which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Svnthesis, 3rd edition, John Wiley and Sons, New York (1999). Examples of hydroxy protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group and the like.
The term xe2x80x9cprotected hydroxyxe2x80x9d refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
xe2x80x9cAmino protecting group,xe2x80x9d as used herein, refers to an easily removable group to which are known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of amino-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, 9-fluorenylmethyl carbamate, benzyl carbonate, tert-butyl carbonate, benzyl, p-toluene sulfonyl, acyl and the like.
The term xe2x80x9caprotic solvent,xe2x80x9d as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley and Sons, NY, 1986.
The term xe2x80x9cprotogenic organic solvent,xe2x80x9d as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley and Sons, NY, 1986.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisoniers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al: describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts; and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussions is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., xe2x80x9cBioreversible Carriers in Drug Designxe2x80x9d, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Susceptibility tests can be used to quantitatively measure the in vitro activity of an antimicrobial agent against a given bacterial isolate. Compounds were tested for in vitro antibacterial activity by a micro-dilution method. Minimal Inhibitory Concentration (MIC) was determined in 96 well microtiter plates utilizing the appropriate Mueller Hinton Broth medium (CAMHB) for the observed bacterial isolates. Antimicrobial agents were serially diluted (2-fold) in DMSO to produce a concentration range from about 64 xcexcg/ml to about 0.03 xcexcg/ml. The diluted compounds (2 xcexcl/well) were then spotted to sterile 96-well microtiter plates. The inoculum for each bacterial strain was adjusted to 5.5xc3x97105 CFU/ml in appropriate MIC medium; 200 xcexcl/well of this inoculum was added to the 96-well microtiter plate resulting in a final concentration of 1xc3x97105 CFU/ml. The 96 well plates were covered and incubated in a humidified atmosphere at 35+/xe2x88x922xc2x0 C. for 16-24 hours depending on the bacterial strain tested. Following incubation, plate wells were visually examined by Optical Density measurement for the presence of growth (turbidity). The lowest concentration of an antimicrobial agent at which no visible growth occurs was defined as the MIC. The compounds of the invention generally demonstrated an MIC in the range from about 64 xcexcg/ml to about 0.03 xcexcg/ml.
All in vitro testing follows the guidelines described in the Approved Standards M7-A5 protocol, published by the National Committee for Clinical Laboratory Standards (NCCLS).
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer""s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylfornamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or other animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to about 50 mg/kg body weight or more usually from 0.1 to about 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment of from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
The pharmaceutical compositions of this invention can be administered to fish by blending them in the fish feed to be administered orally or may be dissolved in water in which sick fish are placed to swim around (a method using a so-called xe2x80x9cmedicated bathxe2x80x9d). The dosage for the treatment of fish differs depending upon the purpose of administration (prevention or cure of disease) and type, size and extent of infection of the fish to be treated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kg of body weight of fish may be administered per day, either at one time or divided into several times. It will be recognized that the above-specified dosage is only a general range which may be reduced or increased depending on the age, body weight, condition of disease, etc. of the fish.
Abbreviations which may be used in the descriptions of the schemes and the examples that follow are: Ac for acetyl; AIBN for azobisisobutyronitrile; Bn for benzyl; Boc for t-butoxycarbonyl; Bu3SnH for tributyltin hydride; Bz for benzoyl; CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC for 1,3-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIC for 1,3-diisopropylcarbodiimide; DMAP for dimethylaininopyridine; DMF for dimethyl formamide; DPPA for diphenylphosphoryl azide; EtOAc for ethyl acetate; KHMDS for potassium bis (trimethylsilyl) amide; LDA for lithium diisopropyl amide; MeOH for methanol; Me2S for dimethyl sulfide; MOM for methoxymethyl; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NCS for N-chlorosuccinimide; NMO for 4-methylmorpholine N-oxide; PCC for pyridinium chlorochromate; PDC for pyridinium dichromate; Ph for phenyl; TEA for triethylamine; THF for tetrahydrofuran; TPP or PPh3 for triphenylphosphine; TBS for tert-butyl dimethylsilyl; TMS for trimethylsilyl.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which are illustrative of the methods by which the compounds of the invention may be prepared. The groups L, X, Z, R1, R2, and Rp are as defined previously unless otherwise noted below. 
Scheme 1 illustrates the processes for the synthesis of compounds of formula (1.6) which serve as preferred intermediates for the preparation of the compounds of formula I. The compounds of the present invention can be prepared by methods which are well known in the art by modification of the readily available compounds of formula (1.1) which can be prepared according to the processes described by Baker et al. J. Org. Chem. 1988, 53, 2340-2345; Elliott et al. J. Med. Chem. 1988, 41, 1651-1659; Ma et al. J. Med. Chem. 2001, 44, 4137-4156, and Or et al. U.S. Pat. No. 6,075,011-B1. Compounds of formula (1.1) are reacted with an acylating reagent to provide compounds of formulas (1.2) and (1.3). Typical acylating conditions include reacting compounds of formula (1.1) with an acid anhydride, a mixed anhydride, an acid halide, a carboxylic acid and the like, optionally in the presence of a catalyst such as DMAP, DDC, DIC or the like, and optionally in the presence of a base such as sodium hydride, potassium tert-butoxide, LDA, KHMDS or the like, in an aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide or the like or a mixture thereof at a temperature of from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 2-48 hours. A preferred acylating condition is reacting compounds of formula (1.1) with a carboxylic acid, DIC, or DMAP in dichloromethane at from 0xc2x0 C. to room temperature. Compounds of formula (1.2), where Y is halogen or another activating group such as mesylate, tosylate or the like, can be converted to compounds of formula (1.3) by reacting with the anion of R2xe2x80x94Xxe2x80x94M where R2 and X are previously defined and M is sodium, potassium, lithium or the like, or R2xe2x80x94Xxe2x80x94H in the presence of a base such as sodium hydride, potassium carbonate, LDA, sodium carbonate, or the likein the presence of an aprotic solvent such as tetrahydroiran, N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide or the like, or a mixture thereof, at a temperature of from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 1-48 hours. Compounds of formula (1.3) undergo an intramolecular cyclization to provide compounds of formula (1.4) upon treatment with a base such as sodium hydride, potassium tert-butoxide, LDA, KHMDS or the like in an aprotic solvent such as tetrahydrofuran; N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide or the like, or a mixture thereof, at a temperature of from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 1-24 hours. The cladinose sugar of the compounds of formula (1.4) is removed by acid hydrolysis upon treatment with dilute hydrochloric acid, sulftric acid, nitric acid, trifluoroacidic acid or the like in an organic solvent such as methanol, ethanol, acetone, water, or the like, or a mixture thereof, at from room temperature to 80xc2x0 C. for 2-48 hours to provide compounds of formula (1.5). Compounds of formula (1.6) are prepared by oxidation of the secondary alcohol of compounds of formula (1.5) using an oxidizing agent. Typical suitable oxidizing agents include, but are not limited to, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (xe2x80x9cDess-Martin reagentxe2x80x9d), NCS/Me2S, TPAP/NMO, PCC, PDC, sulfur trioxide pyridine complex in DMSO, or oxalyl chloride in DMSO, and the like (see, J. March, Advanced Organic Chemistry 4th ed., Wiley and Son, Inc., 1992, and the references therein) in an aprotic solvent such as methylene chloride, ethylene chloride, THF, chloroform, DMF, acetonitrile or the like at a temperature from about xe2x88x9220xc2x0 C. to 50xc2x0 C. for about 1 to 48 hours. 
Another process for the preparation of intermediates of formula (1.6) involves hydrolyzing compounds of formula (2.1) (repared according to Ma et al. J. Med. Chem. 2001, 44, 4137-4156 and Or et al. U.S. Pat. No. 6,075,011-B1) with dilute hydrochloric acid, sulfuric acid, nitric acid, trifluoroacidic acid or the like in an organic solvent such as methanol, ethanol, acetone, water or the like, or mixtures thereof, at from room temperature to 80xc2x0 C. for 248 hours to provide compounds of formula (2.2). Compounds of formula (2.3) are prepared by oxidation of the secondary alcohol of compounds of formula (2.2) using an oxidizing agent. Ttypical suitable oxidizing agents include, but are not limited to, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (xe2x80x9cDess-Martin reagentxe2x80x9d), NCS/Me2S, TPAP/NMO, PCC, PDC, sulfur trioxide pyridine complex in DMSO, or oxalyl chloride in DMSO, and the like (see, J. March, Advanced Organic Chemistry 4th ed., Wiley and Son, Inc., 1992, and the references cited therein) in an aprotic solvent such as methylene chloride, ethylene chloride, THF, chloroform, DMF, acetonitrile or the like at a temperature from about xe2x88x9220xc2x0 C. to about 50xc2x0 C. for about 1 to 48 hours. Compounds of formula (2.4) are prepared by reaction with a sulfonyl reagent such as methane sulfonic anhydride, methane sulfonyl chloride, toluene sulfonyl chloride and the like optionally in the presence of a base such as DMAP, pyridine, triethylamine, sodium hydride, LDA, or the like in an aprotic solvent such as dichloromethane, chloroform, tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, pyridine, or the like, or mixtures thereof, at a temperature from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 2-48 hours to provide the an activated sulfonyl intermediate which is further treated with DBU, potassium tert-butoxide, KHMDS, or the like in an organic solvent such as dichloromethane, tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or the like at a temperature from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 2-48 hours. Compounds of formula (2.5) are prepared by reacting compounds of formula (2.4) with an acid anhydride, a mixed anhydride, an acid halide, a carboxylic acid or the like, optionally in the presence of a catalyst such as DMAP, DDC, DIC or the like and optionally in the presence of a base such as sodium hydride, potassium tert-butoxide, LDA, KHMDS or the like in an aprotic solvents such as dichloromethane, chloroform, tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide or the like, or mixtures thereof, at a temperature from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 2-48 hours. A preferred acylating condition is reacting compounds (2.4) with a carboxylic acid, DIC, or DMAP in dichloromethane at from 0xc2x0 C. to room temperature to provide compounds of formula (2.5). Compounds of formula (2.5) undergo an intramolecular cyclization to provide compounds of formula (1.6) upon treatment with a base such as sodium hydride, potassium tert-butoxide, LDA, KHMDS or the like in an aprotic solvent such as tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide or a mixture thereof or the like at a temperature from xe2x88x9220xc2x0 C. to 50xc2x0 C. for 1-24 hours. 
Scheme 3 illustrates the procedure by which compounds of formula (1.6) may be converted to compounds of formula I by treatment with a halogenating reagent by the process disclosed in U.S. Pat. No. 6,124,269 and International Patent WO 00/62783, which are hereby incorporated by reference herein in their entirety. The halogenating reagent acts to replace a hydrogen atom with a halogen atom at the C-2 position of the ketolide. Various halogenating reagents may be used for this procedure.
Suitable fluorinating reagents include, but are not limited to, N-fluorobenzenesulfornimide in the presence of base, 10% F2 in formic acid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate, 3,5-dichloro-1-fluoropyridinium triflate, (CF3SO2)2NF, N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base, N-fluoropyridinium triflate and N-fluoroperfluoropiperidine in the presence of base.
Suitable chlorinating reagents include, but are not limited to, hexachloroethane in the presence of base, CF3CF2CH2ICl2, SO2Cl2, SOCl2, CF3SO2Cl in the presence of base, Cl2, and NaOCl in the presence of acetic acid.
Suitable brominating reagents include, but are not limited to, Br2.pyridine.HBr, Br2/acetic acid, N-bromosuccinimide in the presence of base, LDA/BrCH2CH2Br, and LDA/CBr4.
Suitable iodinating reagents, include but are not limited to, N-Iodosuccinimide in the presence of base and I2.
Suitable bases for the halogenating reactions requiring them are compounds such as, for example, alkali metal hydrides such as NaH and KH, and amine bases such as LDA or triethylamine. As is well known in the art, different reagents may require a different type of base.
A preferred halogenating reagent is N-fluorobenzenesulfonimide in the presence of xe2x80x94sodium hydride.
Suitable solvents for use in the halogenating reactions are dimethylformamide, dimethyl sulfoxide, pyrrolidinone and the like.
Alternatively, the C-2 position of the compounds of formula 2.1 can be methylated by treatment with a methyl halide in the presence of a base such as K2CO3, NaOH, NaH, LDA or the like, with or without a phase transfer catalyst such as tetrabutylammonium iodide, or the like, in THF, methylene chloride, DMF, DMSO, water or the like, or combinations thereof, at from about 0xc2x0 C. to about 50xc2x0 C. for 1-24 hours to provide compounds of formula I. The Rp protecting group of the compounds of formula I can be removed upon treatment with methanol at from room temperature to 50xc2x0 C.